The objectives of the proposed research are to develop improved molecular probes for specific cocaine recognition sites in brain and to provide fundamental information on the neuropharmacology of these sites in relation to cocaine abuse. Although [3H]cocaine has been a useful tool for characterizing cocaine recognition sites in tissue preparations with high site density, its relatively low affinity and rapid dissociation rate limit its suitability as a molecular probe for further research (e.g., determining regional distribution and labeling solubilized material). Recent studies in our laboratory have revealed that selected fluorophenyltropane analogs of cocaine and phenylindan derivatives have considerably greater affinity for cocaine recognition sites than does cocaine itself. These drugs will be used as precursors to develop novel radioligands and photoaffinity probes for cocaine recognition sites. Candidate drugs first will be assessed for cocaine-like biological activity in vitro by conducting competition studies with specifically bound C3H]cocaine in brain membranes of monkeys and in vivo by determining their effects on schedule-controlled behavior, their substitution for cocaine in drug-discrimination experiments, and their capacity to maintain i.v. self-administration in monkeys. Drugs with full cocaine-like activity will be tritiated, and binding sites labeled by the novel probes will be characterized in brain membranes. Radioligands with improved affinity and dissociation rates subsequently will be used to assess regional distribution of sites by quantitative autoradiography. The novel radioligands also will be used to characterize binding sites in solubilized membranes from selected brain regions. Lastly, photoaffinity probes based on the novel ligands will be developed and used to investigate the molecular structure of the recognition-site complex. The proposed research will provide needed information relevant for isolating cocaine receptors and for developing rational approaches to the pharmacological management of cocaine abuse.